sensorineural hearing loss

Short Stature, Hearing Loss, Retinitis Pigmentosa, and Distinctive Facies

Clinical Characteristics
Ocular Features: 

Two of 3 patients from 2 unrelated German families had myopia and the fundus changes of retinitis pigmentosa.  One was a 28-year-old male and the other was a 44-year-old female from the other family.  In addition, the female was described as having a corneal dystrophy and glaucoma and the male was noted to have nystagmus.

Systemic Features: 

Patients have a marked shortness of stature which may be evident in the first years of life.   Brachydactyly with broad thumbs is present.  Mild intellectual disability is usually a feature as are a high forehead, deep-set eyes, short and upslanting palpebral fissures, and a short nose with anteverted nares. A wide nasal base with thin upper lips, and low-set posteriorly rotated ears may be noted.  Speech is usually delayed and a progressive sensorineural hearing loss may develop in the first few years of life.  Patients appear to age prematurely with sparse hair and arterial hypertension.

MRI imaging may reveal cerebellar atrophy and dysmyelination.  One individual had calcifications in the basal ganglia and thalamus.

Genetics

Homozygous or compound heterozygous mutations in the EXOSC2 gene (9p34) are responsible for this condition.Homozygous or compound heterozygous mutations in the EXOSC2 gene (9p34) are responsible for this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mutations in EXOSC2 are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt

Di Donato N, Neuhann T, Kahlert AK, Klink B, Hackmann K, Neuhann I, Novotna B, Schallner J, Krause C, Glass IA, Parnell SE, Benet-Pages A, Nissen AM, Berger W, Altmuller J, Thiele H, Weber BH, Schrock E, Dobyns WB, Bier A, Rump A. Mutations in EXOSC2 are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt. J Med Genet. 2016 Jun;53(6):419-25.

PubMed ID: 
26843489

Leukodystrophy, Hypomyelinating, 15

Clinical Characteristics
Ocular Features: 

Severe optic atrophy with marked vision loss is commonly present.  Hypermetropia and nystagmus have also been reported.

Systemic Features: 

The clinical features of 4 unrelated patients are highly variable.  Onset of clinical signs is also variable and most are progressive.   Several patients have presented in the first month of life with microcephaly and delayed motor development.  Progressive cerebellar signs of ataxia with dystonia, dysphagia and motor signs from infancy has been seen.  Other patients with cognitive deterioration and progressive neurologic deficits may present late in the first decade of life at which time ataxia, dysarthria, spasticity, and pyramidal signs nay also be noted.  Dystonic and athetoid movements and intention tremor have been reported in some patients.

Brain MRIs in older individuals in the second decade of life reveal hypomyelinating leukodystrophy with thinning of the corpus callosum and cerebellar atrophy.

Genetics

Homozygous or compound heterozygous mutations in the EPRS (1q41) gene are responsible for this autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

Heimler Syndrome 1

Clinical Characteristics
Ocular Features: 

Some patients have mottling of the retinal pigment and features of macular dystrophy.

Systemic Features: 

Primary dentition seems to be normal but secondary teeth have generalized enamel hypoplasia.  Severe bilateral sensorineural hearing loss has been diagnosed in the first or second year of life.  The toenails have transverse ridges (Beau lines) and the fingernails exhibit leukonychia.

Due to the small number of reported families, there is some uncertainty regarding the specificity of the clinical features among the Heimler 1 and Heimler 2 syndromes.

Genetics

Biallelic mutations in the PEX1 gene (7q21.2) are responsible for this syndrome.

Heimler Syndrome 2 (616617) seems to be a unique disorder of peroxisome biogenesis resulting from biallelic mutations in the PEX6 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Spectrum of PEX1 and PEX6 variants in Heimler syndrome

Smith CE, Poulter JA, Levin AV, Capasso JE, Price S, Ben-Yosef T, Sharony R, Newman WG, Shore RC, Brookes SJ, Mighell AJ, Inglehearn CF. Spectrum of PEX1 and PEX6 variants in Heimler syndrome. Eur J Hum Genet. 2016 Nov;24(11):1565-1571.

PubMed ID: 
27302843

Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6

Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CE, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, Van Camp G. Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6. Am J Hum Genet. 2015 Oct 1;97(4):535-45.

PubMed ID: 
26387595

Macular dystrophy in Heimler syndrome

Lima LH, Barbazetto IA, Chen R, Yannuzzi LA, Tsang SH, Spaide RF. Macular dystrophy in Heimler syndrome. Ophthalmic Genet. 2011 Jun;32(2):97-100.

PubMed ID: 
21366429

Spastic Paraplegia 5A

Clinical Characteristics
Ocular Features: 

Gaze-evoked nystagmus and saccadic pursuit movements are present in about 10% of patients.  Optic atrophy was reported in one individual.  Rare patients have been reported to have cataracts.  

Systemic Features: 

This is a progressive disorder of neurological deterioration.  Age of onset (mean 16.4 years) and rate of neurological dysfunction are highly variable.  Gait difficulties are the most common presenting signs.  Some gait ataxia is usually present.  The lower limbs are more severely affected by spasticity and weakness and walking is often delayed with difficulty running and clumsiness in childhood.  Some patients (38%) are wheelchair-bound after disease duration of more than 33 years.  Dysphagia and dysarthria are uncommon. 

Some sensory impairments such as impaired vibratory sense, decreased proprioception, and absent touch sensation in the lower extremities are frequently present.  Urge incontinence of bladder and rectum is sometimes a feature.

Genetics

Bialllelic mutations in the CYP7B1 gene (8q12.3) have been identified in this disorder resulting in a marked accumulation of neurotoxic oxysterols in plasma and CSF.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment for the general disorder has been reported.

References
Article Title: 

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial

Schols L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jagle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Hoflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Zuchner S, Bassi MT, Klopstock T, De Jonghe P, Bjorkhem I, Schule R. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain. 2017 Dec 1;140(12):3112-3127.

PubMed ID: 
29126212

CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5

Goizet C, Boukhris A, Durr A, Beetz C, Truchetto J, Tesson C, Tsaousidou M, Forlani S, Guyant-Marechal L, Fontaine B, Guimaraes J, Isidor B, Chazouilleres O, Wendum D, Grid D, Chevy F, Chinnery PF, Coutinho P, Azulay JP, Feki I, Mochel F, Wolf C, Mhiri C, Crosby A, Brice A, Stevanin G. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain. 2009 Jun;132(Pt 6):1589-600.

PubMed ID: 
19439420

Brown-Vialetto-Van Laere Syndrome 2

Clinical Characteristics
Ocular Features: 

Decreased vision, optic atrophy, and nystagmus are frequently present.  Pupillary reflexes may be absent.

Systemic Features: 

Rapidly progressive muscle weakness and ataxia present in childhood.  Early development may be normal but the first symptoms usually appear by age 2 or 3 years of age.  Cognition is usually normal.  Exercise intolerance soon appears along with dysphonia, dyspnea, dysphagia, and weakness of shoulder, neck and axial muscles.  Wasting and weakness of hand muscles is often noticeable.  Kyphoscoliosis, tongue fasciculations, and areflexia are often seen.  Sensorineural hearing loss is a common feature.

Death from respiratory insufficiency often occurs within a few years after onset.

Genetics

Homozygous mutations in the SLC52A2 (8q24.3) gene have been identified in patients with this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Administration of riboflavin has been reported to be beneficial in lessening symptoms.

References
Article Title: 

SLC52A2 mutations cause SCABD2 phenotype: A second report

Babanejad M, Adeli OA, Nikzat N, Beheshtian M, Azarafra H, Sadeghnia F, Mohseni M, Najmabadi H, Kahrizi K. SLC52A2 mutations cause SCABD2 phenotype: A second report. Int J Pediatr Otorhinolaryngol. 2018 Jan;104:195-199.

PubMed ID: 
29287867

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-Odaib A, Abrams AJ, Sugano K, Yonezawa A, Manzur AY, Burns J, Hughes I, McCullagh BG, Jungbluth H, Lim MJ, Lin JP, Megarbane A, Urtizberea JA, Shah AH, Antony J, Webster R, Broomfield A, Ng J, Mathew AA, O'Byrne JJ, Forman E, Scoto M, Prasad M, O'Brien K, Olpin S, Oppenheim M, Hargreaves I, Land JM, Wang MX, Carpenter K, Horvath R, Straub V, Lek M, Gold W, Farrell MO, Brandner S, Phadke R, Matsubara K, McGarvey ML, Scherer SS, Baxter PS, King MD, Clayton P, Rahman S, Reilly MM, Ouvrier RA, Christodoulou J, Zuchner S, Muntoni F, Houlden H. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain. 2014 Jan;137(Pt 1):44-56.

PubMed ID: 
24253200

Ayme-Gripp Syndrome

Clinical Characteristics
Ocular Features: 

Most patients have congenital cataracts which may be mild and "oil drop" in appearance.  The eyes appear far apart, the eyebrows are broad, and the palpebral fissures may slant upward or downward.  Ptosis has been reported.  Aphakic glaucoma has been reported in one juvenile who had unilateral cataract surgery at 5 months of age.

Systemic Features: 

The phenotype is heterogeneous and not all patients have all features.  The facial features are said to resemble those of the Down syndrome with brachycephaly, a high forehead, and a flat midface with shallow orbits and malar hypoplasia.  The ears are small, low-set, and posteriorly rotated.  The nose is short and the nasal bridge is broad and flat.  The mouth is small and the upper lip is thin.  The scalp hair may be sparse and the nails sometimes appear dystrophic.

The fingers are sometimes brachydactylous and tapered.  Short stature is common and the joints may have limited motion.  Dislocation of the radial heads is seen rarely while radioulnar synostosis has been seen in a few individuals.  Postnatal short stature is common.

Seizures often occur.  The ventricles appear large and cerebral atrophy has been reported.  Intellectual disability and mental retardation are common. However, at least one individual attended university although he had been diagnosed in childhood with Asberger disease.   Neurosensory hearing loss is common.

Genetics

This autosomal dominant condition results from heterozygous mutations in the MAF (16q32.2) gene.  At least one mother/son transmission event has been reported.

Many of the same features are seen in what has been called the Fine-Lubinsky syndrome (601353) but without mutations in the MAF gene.  It may not be a unique disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment has been reported but specific anomalies such as cataracts should be addressed.

References
Article Title: 

Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies

Niceta M, Stellacci E, Gripp KW, Zampino G, Kousi M, Anselmi M, Traversa A, Ciolfi A, Stabley D, Bruselles A, Caputo V, Cecchetti S, Prudente S, Fiorenza MT, Boitani C, Philip N, Niyazov D, Leoni C, Nakane T, Keppler-Noreuil K, Braddock SR, Gillessen-Kaesbach G, Palleschi A, Campeau PM, Lee BH, Pouponnot C, Stella L, Bocchinfuso G, Katsanis N, Sol-Church K, Tartaglia M. Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies. Am J Hum Genet. 2015 May 7;96(5):816-25.

PubMed ID: 
25865493

Cone-Rod Dystrophy with Hearing Loss

Clinical Characteristics
Ocular Features: 

Patients note reduced vision in brightly-lit environments with onset in early adulthood and progressive central vision loss thereafter.   Nystagmus, photophobia, and dyschromatopsia may be present.  Younger individuals may complain of night blindness.  Visual fields show diffuse progressive suppression with relative sparing of selected areas such as the peripapillary region.  The ERG documents primary cone dystrophy but less involvement of the rods.  EOG testing in 4 patients showed reduced light-dark ratios.  Macular degeneration, attenuated vessels, subtle salt-and-pepper pigmentation, and spicular pigmentary deposits in the mid-periphery may be seen.

Systemic Features: 

The hearing loss is sensorineural in nature and can be progressive from its onset in childhood.

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the CEPL78 (9q21.2) gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the basic condition has been reported.  Assistive hearing devices and tinted lenses could be helpful.

References
Article Title: 

Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects

Nikopoulos K, Farinelli P, Giangreco B, Tsika C, Royer-Bertrand B, Mbefo MK, Bedoni N, Kjellstrom U, El Zaoui I, Di Gioia SA, Balzano S, Cisarova K, Messina A, Decembrini S, Plainis S, Blazaki SV, Khan MI, Micheal S, Boldt K, Ueffing M, Moulin AP, Cremers FP, Roepman R, Arsenijevic Y, Tsilimbaris MK, Andreasson S, Rivolta C. Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects. Am J Hum Genet. 2016 Sep 1;99(3):770-6.

PubMed ID: 
27588451

CEP78 is mutated in a distinct type of Usher syndrome

Fu Q, Xu M, Chen X, Sheng X, Yuan Z, Liu Y, Li H, Sun Z, Li H, Yang L, Wang K, Zhang F, Li Y, Zhao C, Sui R, Chen R. CEP78 is mutated in a distinct type of Usher syndrome. J Med Genet. 2016 Sep 14. pii: jmedgenet-2016-104166. doi: 10.1136/jmedgenet-2016-104166.

PubMed ID: 
27627988

Mitochondrial DNA Depletion Syndrome 1

Clinical Characteristics
Ocular Features: 

Progressive external ophthalmoplegia has an adult onset, usually in the late second or early third decade of life.  Ptosis is commonly present as well.

Systemic Features: 

This condition has been called a mitochondrial neurogastrointestinal encephalopathy (MNGIE).  Gastrointestinal problems are among the most disabling with poor absorption of foodstuffs leading to weight loss, marked cachexia, and chronic malnutrition.  Added to this are gastroparesis, constipation, vomiting, and intermittent diarrhea with abdominal pain.  Many individuals develop diverticulosis and diverticulitis that may lead to intestinal perforations.  The combined intestinal dysfunctions can lead to signs of intestinal pseudoobstruction.

Many patients have a progressive sensorineural hearing loss.  Leukoencephalopathy, sensorimotor peripheral neuropathy, and sometimes mild proximal limb weakness may be present.

Genetics

Homozygous and compound heterozygous mutations in the TYMP gene (22q13.33) are responsible for this autosomal recessive disorder.  This nuclear gene is active in the maintainence of mitochondrial DNA.  When the gene is dysfunctional, the mitochondria can be depleted to a variable extent and they may contain multiple deletions and point mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment for the overall condition.  Nutritionists can provide important advice on diet to maintain good nutrition.  Regular monitoring by gastroenterologists is important.  Perforations of the bowels require prompt surgical repair.  

References
Article Title: 

Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations

Nishino I, Spinazzola A, Papadimitriou A, Hammans S, Steiner I, Hahn CD, Connolly AM, Verloes A, Guimaraes J, Maillard I, Hamano H, Donati MA, Semrad CE, Russell JA, Andreu AL, Hadjigeorgiou GM, Vu TH, Tadesse S, Nygaard TG, Nonaka I, Hirano I, Bonilla E, Rowland LP, DiMauro S, Hirano M. Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol. 2000 Jun;47(6):792-800.

PubMed ID: 
10852545

Duane Retraction Syndrome 3

Clinical Characteristics
Ocular Features: 

This type of Duane syndrome usually has limitation of both abduction and adduction.  It may be unilateral but more often is bilateral.  Attempted adduction is accompanied by globe retraction and narrowing of the lid fissure.  MRI and postmortem examination reveals absence or hypoplasia of the abducens nerve with aberrant innervation of the lateral rectus by the oculomotor nerve in some individuals with Duane retraction syndrome.  

Amblyopia is a risk.

Systemic Features: 

Sensorineural hearing loss (unilateral or bilateral) may accompany the strabismus profile as reported among 3 of 4 individuals in a single family.  CT imaging of the temporal bone in one patient revealed a cystic common-cavity anomaly.

Genetics

Type 3 Duane syndrome is an autosomal dominant condition resulting from heterozygous mutations in the MAFB gene (20q12).  Both single base pair and full gene deletions cause loss of gene function and a dominant-negative effect.

This database also contains two additional forms of  autosomal dominant isolated Duane syndrome: DURS 1 (126800) and DURS 2 (604356).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Extraocular muscle surgery may improve ocular motility.  Monitoring for amblyopia is important with appropriate treatment as indicated.  Assistive hearing devices may be beneficial.  

References
Article Title: 

Progeroid Short Stature with Pigmented Nevi

Clinical Characteristics
Ocular Features: 

The presence of cataract has been reported.   One patient with keratoconus, endothelial dystrophy, and chronic conjunctivitis required a corneal transplant for a perforated ulcer.  Another individual with endothelial dystrophy, keratoconus, dry eye syndrome, and conjunctivitis developed OCT evidence of progressive retinal thickening and folding of inner retinal layers.  Retinal electrodiagnostic tests were normal.   Few patients have had complete ocular examinations, however.

Systemic Features: 

Short stature beginning in utero is characteristic and general growth parameters are usually in the third percentile.  The appearance of premature aging is suggested by a pinched bird-like facies and lack of facial subcutaneous fat.  Striking cutaneous pigmented nevi are present and may increase in number throughout life.  Joint mobility is limited to about half of normal.  The voice is often characteristically high-pitched.  Hypodontia and irregular dentition are often seen.

There may be an immunodeficiency as reflected by susceptibility to recurrent infections due to subnormal numbers of B and T cells.  Cognitive abilities are subnormal and some decline in adulthood has been reported.  Some individuals have been considered mentally retarded.  Agitation, touch hypersensitivity, depression, panic attacks, and severe insomnia may be present.  Sensorineural hearing loss is common.  Males may have hypospadias while females experience premature puberty and premature menopause.

Genetics

Consanguinity among some parents suggests autosomal recessive inheritance but no locus or mutation have been identified.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatnent has been reported.

References
Article Title: 

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